Palladium-catalyzed synthesis of carbazoles from N-(2-halophenyl)-2,6-diisopropylanilines via C-C cleavage

Article abstract of DOI:10.1016/j.tetlet.2010.02.098

The synthesis of 1-isopropyl-substituted carbazoles by the palladium-catalyzed dealkylative cyclization of N-(2-halophenyl)-2,6-diisopropylanilines is described. The reaction involves intramolecular C-C bond formation, coupled with the cleavage of a C-X bond and a C-C bond, and is proposed to proceed through the formation of a dearomatized intermediate.

Full text of DOI:10.1016/j.tetlet.2010.02.098

Tetrahedron Letters 51 (2010) 2241–2243
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Palladium-catalyzed synthesis of carbazoles from
N-(2-halophenyl)-2,6-diisopropylanilines via C–C cleavage
*
Anthony R. Chianese , Scott L. Rogers, Hanna Al-Gattas
Chemistry Department, Colgate University, 13 Oak Drive, Hamilton, NY 13346, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
The synthesis of 1-isopropyl-substituted carbazoles by the palladium-catalyzed dealkylative cyclization
of N-(2-halophenyl)-2,6-diisopropylanilines is described. The reaction involves intramolecular C–C bond
formation, coupled with the cleavage of a C–X bond and a C–C bond, and is proposed to proceed through
the formation of a dearomatized intermediate.
Received 26 January 2010
Accepted 17 February 2010
Available online 21 February 2010
Ó 2010 Elsevier Ltd. All rights reserved.
Keywords:
Palladium
Catalysis
Carbazoles
Cyclization
The palladium-catalyzed formation of carbon–carbon bonds via
intramolecular C–X/C–H cross-coupling1,2 has emerged as an effi-
cient and versatile method for the synthesis of carbazoles, as well
as a variety of other heterocycles and carbocycles. Analogous cycli-
zations involving C–C cleavage3 rather than C–H cleavage have not
been demonstrated, however. The development of catalytic trans-
formations involving carbon–carbon bond cleavage is challenging,
though several successful strategies have been advanced, involving
the relief of ring strain, chelation assistance, and b-hydrocarbyl
elimination.4,5
In the course of the synthesis of a series of bidentate N-hetero-
cyclic carbene–pyridine ligands,6 we attempted the palladium-cat-
alyzed mono-amination of 4,5-dibromoveratrole with 2,6-
diisopropylaniline, employing the conditions reported by Bielawski
and co-workers,7 which provide highly efficient tetra-aminations
of 1,2,4,5-tetrabromobenzene (Scheme 1). The expected product
1 was not formed in a significant amount; instead we isolated
the carbazole 2 in 25% yield, formed via loss of an ortho-isopropyl
group, whose structure has been confirmed by X-ray crystallogra-
phy.8 This unexpected transformation warranted further investiga-
tion because the cleaved sp2–sp3 carbon–carbon bond is
unactivated and sterically hindered. Herein, we report the studies
on the scope of this reaction and discuss a possible mechanism
for the formation of the carbazole product.
pyl group. As such, we exposed the minimally functionalized sub-
strate 1a to similar conditions (Table 1, entry 1), and were pleased
to observe smooth formation of the carbazole product 2a. This
transformation is closely related to palladium-catalyzed cycliza-
tions of 2,6-dimethyl-substituted N-(2-bromophenyl)-anilines, re-
cently reported by Bedford et al.9 In the Bedford study, carbazole
formation results from the cleavage of an ortho-methyl group,
which competes with an unusual [2+2] cyclodimerization process.
In contrast, carbazole 2a was the sole product observed in the
crude NMR spectrum when 1a was subjected to the conditions
shown in Scheme 1.
For optimization of the reaction parameters, we focused on sub-
strate 1a, varying the base, solvent, ligand, and palladium source
(Table 1). Of several bases commonly employed in palladium-cat-
alyzed cross-coupling, only NaOtBu was effective (entries 1–4).
Toluene was an effective solvent, but no formation of 2a was ob-
served using either dioxane or N-N0-dimethylformamide (entries
5 and 6). A screen of several commercially available ligands
(entries 7–14) revealed that only bulky, monodentate phosphines
9% Pd(OAc)2
18% SIPr HCl
5 NaOtBu
Br
Br
H2N
+
HN
HN
+
Presumably, the first step in carbazole formation is the origi-
nally expected mono-amination reaction giving 1, followed by
C–C bond-forming cyclization with loss of bromide and the isopro-
toluene
Br
OMe
MeO
OMe
110 oC, 48 h
OMe
OMe
1, not isolated
MeO
2, 26%
* Corresponding author. Tel.: +1 315 228 7718; fax: +1 315 228 7935.
E-mail address: achianese@colgate.edu (A.R. Chianese).
Scheme 1. Unexpected formation of carbazole.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.02.098

2242
A. R. Chianese et al. / Tetrahedron Letters 51 (2010) 2241–2243
Table 1
Table 2
Survey of conditionsa
Cyclization of various substratesa
5% [Pd]
10% ligand
3 equiv. base
Br
H
Entry
Reactant
Product
H
N
N
H
Br
H
N
solvent
110 oC, 24 h
N
2a
1
1a
2a, 73%
Entry
Base
Solvent
Ligand
Pd source
Yield (%)
1a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
NaOtBu
CsCO3
NaOMe
K3PO4
Toluene
Toluene
Toluene
Toluene
Dioxane
DMF
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
SIPrꢀHCl
PPh3
DPEPhos
SPhos
BINAP
PCy3
dppp
SIMesꢀHCl
PtBu3ꢀHBF4
SIPrꢀHCl
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
73
8
0
4
0
0
0
0
62
0
34
0
0
37
77
Cl
Cl
H
N
2
3
4
2a, 73%
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
1b
H
N
H
N
F3C
2c, 47%
CF3
Cl
b
1c
Pd2(dba)3
H
N
a
Yields were measured by GC, using tetradecane as internal standard.
Loading of Pd2(dba)3 was 2.5 mol %.
H
N
b
MeO
2d, 63%b
MeO
promote the formation of the carbazole. The monodentate phos-
phine ligand SPhos10 was effective (entry 9), while PCy3 and PtBu3
were somewhat effective (entries 11 and 14). Bidentate ligands are
completely ineffective (entries 8, 10, and 12). Surprisingly, the N-
heterocyclic carbene ligand SIMesꢀHCl is completely ineffective
(entry 13), although the structurally similar SIPrꢀHCl was the most
effective (entry 1). Pd2(dba)3 was approximately equally effective
as palladium source, as compared to Pd(OAc)2 (entry 1 vs entry 15).
With optimized conditions in hand, we set out to examine the
scope of the reaction (Table 2). The chloro-substituted substrate
1b was efficiently transformed to 2a. Substitution of the arene
backbone with electron-withdrawing (1c) or electron-donating
(1d) groups gave a moderately less efficient transformation. Sub-
strate 1e, with an ortho-methyl substituent, was converted much
more slowly. Only a trace amount of carbazole 2e was formed un-
der the standard conditions, but a short screen of bulky monoden-
tate ligands revealed that PCy3 promotes the cyclization, albeit
extremely inefficiently (entry 5). Substrate 1f, with only one
ortho-isopropyl substituent, gave exclusive C–H cleavage: carba-
zole 2a was isolated in 29% yield under the standard conditions,
while unsubstituted carbazole that would be formed via C–C cleav-
age was not observed in the crude reaction mixture, by NMR or
GC–MS. This indicates that in intramolecular competition, the pre-
viously known cyclization via C–H cleavage11–17 is significantly
faster than the presently studied transformation.
1d
H
Cl
N
H
N
5
6
2e, 14%c
1e
Br
Br
H
N
2a, 29%
1f
H
N
N
H
7
H
1g
N
3g, 60%
a
Reaction conditions: Amine (0.40 mmol), Pd(OAc)2 (5 mol %), SIPrꢀHCl (10 mol %),
and NaOtBu (3 equiv) in toluene (35 mL). Stirred at 110 °C for 20 h. Isolated yields
are given.
b
Performed using 10% Pd(OAc)2 and 20% SIPrꢀHCl.
c
Performed using 10% Pd(OAc)2 and 20% PCy3.
Light was shed on the mechanism of this unusual transforma-
tion when the 2,6-diethyl-substituted substrate 1g was subjected
to the standard conditions. No carbazole (2g) was formed; rather,
the dimerized product 3g was isolated in 60% yield. X-ray crystal-
lography confirmed the structure as a Diels–Alder dimer of the
putative initial product 4 (Scheme 2, top). Analysis of the crude
reaction mixture by 1H NMR and thin-layer chromatography con-
firms the presence of a compound that is converted to 3g upon
concentration, whose 1H NMR spectrum is consistent with that of
structure 4. Presumably, 4 is formed via a palladium-catalyzed
dearomatization, and dimerizes upon rotary evaporation at ele-
vated temperature. Attempts to isolate 4 in pure form were ham-
pered by dimerization to 3g. Analysis of the crude reaction
mixtures for the isopropyl-substituted substrates 1a–e by GC–MS
and 1H NMR showed no analogous dearomatized intermediate. In
the recent study by Bedford et al.,9 substrate 1g was transformed
to 1-ethyl-9H-carbazole via cleavage of an ethyl group under
nearly identical conditions to those in Table 2, in complete contrast
to our observations. The key difference appears to be the reaction
workup: our workup consisted of filtering the reaction mixture
through a plug of silica gel, while the authors of the prior study
employed acidic aqueous conditions.
The putative formation of product 4 is also analogous to a trans-
formation of N-aryl-naphthylamines recently reported by Buch-
wald and co-workers,18 promoted by the combination of
palladium, a bulky monodentate phosphine, and a t-butoxide salt
(Scheme 2, bottom). The authors proposed the reaction mechanism
shown in Scheme 3, which is consistent with our observations and

A. R. Chianese et al. / Tetrahedron Letters 51 (2010) 2241–2243
2243
5% Pd(OAc)2
10% SIPr HCl
3 NaOtBu
are formed initially, then are transformed to 2a–e by the loss of
the isopropyl group, presumably by an SN1 mechanism, followed
by protonation at nitrogen.
Br
H
N
N
3g
In summary, we have described a novel palladium-catalyzed
transformation, where 2-halo-N-(2,6-diisopropylphenyl)anilines
cyclize to give carbazoles via C–X/C–C cross-coupling. In the pro-
posed mechanism, palladium facilitates the formation of a dearo-
matized carbazole intermediate; rearomatization then provides
the driving force for carbon–carbon bond cleavage and the forma-
tion of the resulting carbazole.
toluene
110 oC, 24 h
4
1g
This work
3% Pd(dba)2
4.5% KenPhos
1.2 LiOtBu
Br
R
Ph
H
N
N
R
Ph
R = H, OMe, CF3, F, Cl
THF
70-100 oC, 15 h
Acknowledgments
The authors are grateful to the Research Corporation for Science
Advancement (CCSA-7106) and the National Science Foundation
Major Research Instrumentation program (CHE-0819686).
Ref. 18
Scheme 2. Formation of dearomatized products.
Supplementary data
LPdBr
R
H
N
Br
R
H
N
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2010.02.098.
tBuO-
A
References and notes
LPd0
L
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B
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with those of the Bedford and co-workers9 study. Initial oxidative
addition at the C–Br bond to LPd0 gives intermediate A. Next,
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bis(diphenylphosphino)xanthene; BINAP = rac-2,20-bis(diphenylphosphino)-1,10-
binaphthyl;
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chloride;
chloride;
dppp = 1,3-
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bis(diphenylphosphino)propane; dba = dibenzylideneacetone.
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